Pharmaceutical preparations containing substituted phenylcarbamic acid esters of cyclic amino alcohols

ABSTRACT

PHARMACEUTICAL PREPARATION CONTAINING CARBAMATES WHICH ARE SUBSTITUTED PHENYLCARBAMIC ACID ESTER OF N-ALKYL-SUBTITUTED CYCLIC AMINO ALCOHOLS OF THE GENERAL FORMULA:   1-(CH3-),2-((-(CH2)N-N-CH2-)&gt;CH-OOC-NH-),3-R1-BENZENE   THESE PREPARATIONS EXHIBIT LOCAL ANESTHETIC EFFECTS.

United States Patent 3,632,766 PHARMACEUTICAL PREPARATIONS CONTAIN- INGSUBSTITUTED PHENYLCARBAlVIIC ACID ESTERS OF CYCLIC AMINO ALCOHOLS JohanRichard Dahlbom, Sodertalje, and John Lars Gunnar Nilsson, Skarholmen,Sweden, assignors to Aktiebolaget Astra, Sodertalje, Sweden No Drawing.Original application Feb. 28, 1968, Ser. No. 708,758, now Patent No.3,544,579, dated Dec. 1, 1970. Divided and this application Aug. 17,1970, Ser. No. 64,616 Claims priority, application Sweden, Mar. 9, 1967,

Int. Cl. A61k 27/00 US. Cl. 424-267 5 Claims ABSTRACT OF THE DISCLOSUREPharmaceutical preparations containing carbamates which are substitutedphenylcarbamic acid esters of N-alkyl-substituted cyclic amino alcoholsof the general formula:

These preparations exhibit local anesthetic effects.

This is a division of application Ser. No. 708,758, filed Feb. 28, 1968now US. Pat. No. 3,544,579.

The present invention relates to pharmaceutical preparations containingcarbamate compounds as active ingredients. More particularly, thisinvention relates to carbamate compounds which are substitutedphenylcarbamic acid esters of cyclic amino alcohols of the generalformula:

0113 G2: YCH 0112 3,632,766 Patented Jan. 4, 1972 wherein R, R and nhave the meaning given above and wherein X and Y are groups capable ofreacting with each other to the formation of the bridge -NHCOO betweenthe two rings.

Examples of different ways of carrying out the present invention are:

(1) Reaction between an isocyanate of the formula,

and an alcohol of the formula,

(2) Transesterification of an ester of the formula,

with said alcohol. (3) Reaction between an acid azide of the formula,

and said alcohol. (4) Reaction between a carbamic acid chloride of theformula,

and said alcohol. (5) Reaction between an amine of the formula,

and a chlorocarbonic acid ester of the formula,

When used as local anesthetics in therapy, the compounds according tothe present invention may be adminis tercd in the form of a sterile,injectable solution of at least one of these compounds in apharmaceutical carrier. The concentration is not important and widelyvarying concentrations are therapeutically effective. Typically, solu- 1tions may contain from about 0.02% up to a high of about activeingredient by weight. The compounds may also be administered in the formof other pharmaceutical preparations, such as Suspensions, jellies,ointments or bases.

In pharmaceutical preparations, one or more of the compounds accordingto the invention may be used in the form of their free bases ortherapeutically acceptable acid addition salts or as both. Theexpression therapeutically acceptable acid addition salt is recognizedin the art to designate an acid addition salt which is physiologicallyinnocuous when administered in a dosage and at an interval (i.e.frequency of administration) that is efifective for the indicatedtherapeutic use of the parent compound. Typical therapeuticallyacceptable acid addition salts of the compounds of the present inventioninclude, but are not limited to, the salts of mineral acids, such ashydrochloric, hydrobromic, phosphoric or sulphuric acid; organic acids,such as acetic, glycolic, lactic, levulinic acid, acetic, fumaric,maleic, succinic, tartaric, benzoic and cinnamic acids; and sulphonicacids, such as methane sulphonic and sulphamic acid.

As is well known in the art, solutions of local anesthetics may be madeisotonic by the addition of sodium chloride. Furthermore, it is known inthe art of local anesthesia that anesthetic effectiveness may beimproved by addition of a vasoconstrictor, such as adrenaline,noradrenaline or octapressin.

The amount of local anesthetic which may be used varies widely and iswell known depending upon the location and type of anesthesia required.The anesthetic eifect, according to the present invention, is induced byapplying an amount of a substituted phenylcarbamic acid ester of cyclicamino alcohols of the present invention which is eflective to producethe desired anesthesia. Repeated applications at therapeuticallyeffective intervals may be made, if desired, to obtain a prolongedanesthetic effect.

The valuable pharmacological properties of the carbamate compounds ofthe present invention are demonstrated in Table 1, wherein the localanesthetic effects of a number of these carbamates is given incomparison with lidocaine, a well-known local anesthetic. The relativeeffect of lidocaine equals 1.0.

TABLE 1 Local anesthetic effect Blocking of Surface anesconductionthetic efiect Toxicity in in isolated on rabbit mice, i.v. R R n frognerve cornea LDsn, rug/kg.

Table 2 shows the results of a number of experiments with guinea pigscomparing the local anesthetic etfects of two compounds according to thepresent invention with lidocaine and bupivacaine, another knownanesthetic which is used chemically as a long-acting local anestheticagent.

TABLE 2.LOCAL ANESTHETIC EFFECTS Peridural anesthesia d Perlduralanesthesia Block of the plexus Duration, rnin.

Sciatic nerve block a brachialis h Duration, rmn. Compound Block ofConc., Duration, Cone, Duration, Cone, Hind-limb Segmental Conc., Deepmotor support of R R 11. percent min. percent min. percent paralysisanalgesla. percent block weight 0. 5 1425:14 0. 215i23 0. 75 123i594:1:5 0. 5 2255:32 170:1:32 G1 04H? 3 i 1. 0 228:1:14 1. 0 41041 t t3385:18

CHM 1:8 i333 "will-..-.??f?....-.9f? j???" ..Y?f.:::::::::: S Bupivacaine 0. 5 1445114 0. 5 132:1:7 0. 5 91:1:6 62:1:8 0. 5 218:1:1514:51:14 Lidocaine 2.0 805:7 2. 0 51i7 2. 0 41:;2 37:1:3 2. 0 :1:688:1:6

* Guinea-pig. Hindlimb paralysis. Injected volume, 0.2 ml. N=8.

b Guinea-pig. Fore-limb paralysis. Solutions with adrenaline 12200000.Injected volume, 0.2 ml. N=8. c Guinea-pig. Solutions containingadrenaline 1:200000. Injected volume, 0.1 ml. N= 16. d Cat. Solutionscontaining adrenaline 1: 100000. In eeted volume, 1.5 ml. N=10.

Norm-N =Number of animals.

In Table 3, the results of camparative tests with frogs, The followingcompounds may be prepared in an mice and guinea pigs to show localanesthetic effects analogous y: and acute toxicity using lidocaine andtwo compounds N-ethyl-3-pyrrolidyl 2,6-dimethylphenylcarbamate;according to the invention are reported: 5 M.P. 57-58.5 C.

TABLE 3.--LOCAL ANESTHETIC EFFECTS AND ACUTE TOXICITY IsolatedIntravenous nerve Sciatic LD oi the nerve Peridural rug/ha Compound frog8 block b anesthesia (base) Lidocaine CH 1. 0 1.0 1. 0 22 NBC 0 CHzNGzHs CH3 HS 37 (I)- CH 1 2.7 3.1 13

NBC 0 O I? C4H9 HS 38 (II) CH 1 2.3 3. 3

NBC 0 O 5 mM solutions. Incubation time, 5 min. N=3. b Guinea-pig. 1.0%solutions. Injected volume 0.2 ml. N=8. Guinea-pig. 1.0% solutions withadrenaline 1:200000. Injected volume, 0.1 ml. N=8.

* Mice. N=70. NOTE. N=Number of animals.

The acceptable toxicity levels of the present inven-N-ethyl-3-pyrrolidyl 2-chloro-6-methylphenylcarbamate; tion aredemonstrated in Table 4. Table 4 reports the p 5 results of furthercomparative experiments on the acute 40 I toxicity of bupivacaine andtwo compounds of the present N n propyw yrrohdyl26'dlmethylphenylcarbamate invention using mice, guinea pigs and rats.

TABLE 4.-ACUTE TOXICITY (LD)5 IN MICE, GUINEA-PIGS AND RATS LDao mgJkg.[base] e Calculated according to Litehfield and Wileoxon (J. Pharmac 96,99 1949). 95 percent confidence intervals (in brackets).

The following examples show methods for preparingN-n-propyl-3-pyrrolidyl 2-chloro-6-methylphenylthe compounds accordingto the present invention and carbamate; M.P. 7l72 C. procedures formaking various pharmaceutical prepara- N-i-propyl-3-pyrrolidyl2,6-dimethy1phenylcarbamate;

tions containing these compounds as active ingredients. M.P. 5758.5 C.

N-i-propyl-3-pyrrolidyl 2-chloro-6-methylphenyl- EMMPLE 1 60 carbamate;M.P. 80-82 C. Prep l 0f l 'PY l N-t-buty1-3-pyrrolidyl2,6-dimethylphenylcarbamate;

methylphenylcarbamate M.P. of the hydrochloride 207208 C.

N-methyl-3-piperidyl 2,6-dimethylphenylcarbamate;

M.P. 101l02 C. N-methyl-3-piperidyl 2-chloro-6-methylpheny1carbamate;

4.65 g. of 2-ch1oro-6-methylphenylisocyanate were added to a solution of4 g. N-t-butyl-3-hydroxypyrrolidine in 75 ml. of dry toluene and thesolution was re- 0 fluxed for 2 hours. After cooling the solution waswashed 120 12 1 twice with 25 ml. portions of water and extracted twiceY 'P Pf Y ylphcnylcarbamate;-M,P, of the with 25 ml. portions of 2 Mhydrochloric acid. The acid hYdTOChIPHd? 245246 extract was madealkaline with soda solution and the N'ethyl'3'plpendyl2:6'dlmethylphenylcafbamate; precipitated base was extracted withchloroform. After evaporation of solvent in vacuo, the crystallineresidue N'ethyl'3'piperidyl 2431110)'fi'methykafbamate; was purified byrecrystallization from ligroin. The pure 83- 4 C. product,N-t-butyl-3-pyrrolidyl 2-chlor0-6-methy1phenyl- N-n-propyl-3-piperidyl2,6-dimethylpheny1carbamate; carbamate, melts at 108-109 C. M.P. 75-76C.

7 N-n-propyl-3-piperidyl 2-chloro-6-methylphenylcarbamate; M.P. 100-101C. N-i-propyl-S-piperidyl 2,6-dimethylphenylcarbamate;

M.P. of the hydrochloride 2092l0 C. N-i-propyl-3piperidyl2-chloro-6-methylphenylcarbamate;

M.P. of the hydrochloride 207208 C. N-t-butyl-3-piperidyl2,6-dimethylphenylcarbarnate;

M.P. 110-1 11 C. N-t-butyl-3-piperidyl 2-chloro-6-methylphenylcarbamate;

M.P. of the hydrochloride 219220 C. N-n-butyl-3-piperidy12-chloro-6-methylphenylcarbamate;

M. P. 76.5-77.5 C. N-n-butyl-3-piperidyl 2,6-dimethylphenylcarbamate;

M.P. of the hydrochloride 122124 C.

EXAMPLE 2 Preparation of N-methyl-3-piperidyl 2-chloro-6-methylphenylcarbamate 0.2 g. of sodium were added to a solution of 12.7g. of ethyl-2-chloro-6-methylphenylcarbamate and 11.6 g. ofN-methyl-3-hydroxypiperidine in 100 ml. of toluene and the reactionmixture was refluxed for 8 hours during which ethanol formed and wasslowly distilled off. The solution was then washed with water andextracted with l N hydrochloric acid. The extract was made alkaline withsodium carbonate and the oily reaction product thereby precipitated wasextracted with ether. On evaporation of the ether, N-methyl-3-piperidyl2-chloro-6-methylphenylcarbarnate was obtained in crystalline form.After recrystallization from a mixture of ethanol and petroleum ether,the product melts at 120-121 C.

EXAMPLE 3 Preparation of N-methyl-3-piperidyl Z-methylphenylcarbamate Asolution of 6.0 g. of o-tolyl azide and 6.5 g. ofN-methyl-3-hydroxypiperidine in 50 ml. of dry benzene was refluxed for 2hours. The solution was then washed twice with 50 ml. of water in orderto remove excess amino alcohol and extracted with 2X 50 ml. of 2 N HCl.The acid extract Was made alkaline with sodium carbonate solution andthen extracted with chloroform. After drying over sodium sulphate, thechloroform was evaporated in vacuum. The residue, a slowly crystallizingoil, was purified by recrystallization from ligroin. The pure product,N-methyl-3-piperidyl Z-methylphenylcarbamate, melts at 9293 C.

EXAMPLE 4 Preparation of N-ethyl-3-piperidyl 2,6-dimethylphenylcarbamate4.9 g. of 2,6-dimethylaniline and 3.2 g. of pyridine were added whilechilling in ice to a solution of 4.0 g. of phosgene in 100 ml. oftoluene. The reaction mixture was kept Preparation ofN-n-propyl-S-piperidyl 2,6-dimethylphenylcarbamate 2.8 g. of phosgenewas added while chilling with ice to a solution of 4 g. ofN-n-propyl-3-hydroxypiperidine in 100 ml. of chloroform. The reactionmixture was left at O-5 C. while stirring, whereafter 3.4 g. of2,6-dimethylaniline and 6 g. of triethylamine were added to the solutionbifiincd containing the hydrochloride of N-n-propyl- 3-hydroxypiperidinechlorocarbonic acid ester. The solution was refluxed for 4 hours,whereafter the solvent was distilled off. The residue was dissolved inwater and the water solution was made alkaline with sodium carbonatesolution. The base precipitated, N-n-propyl-3-piperidyl 2,6-dimethylphenylcarbamate, was extracted with ether. The ether solutionwas Washed with Water in order to remove triethylamine and dried oversodium sulphate. After evaporation of the solvent the residue waspurified by recrystallization from petroleum ether. M.P. 76 C.

EXAMPLE 6 Injectable solution containing N-n-butyl-3-piperidyl-2-chloro-6-methylphenylcarbamate hydrochloride To 100 ml. of hot,sterilized water, 0.1 g. of methyl p-hydroxybenzoate were added whilestirring and heating. When all benzoate was dissolved, 2 g. ofN-n-butyl-3- piperidyl 2 chloro 6 methylphenylcarbamate hydrochlorideand 0.9 g. of sodium chloride were added while stirring. The pH wasadjusted to 5.5 by adding sodium hydroxide. Sterilized water was addedto 100 ml.

EXAMPLE 7 Injectable solution containing N-n-butyl-3-piperidyl-2-chloro-6-methylphenylcarbamate hydrochloride and vasoconstrictor To 100ml. of hot, sterilized water, 0.1 g. of methyl p-hyroxybenzoate, 2 g. ofN-n-butyl-3-piperidyl-2-cholor- 6-methylphenylcarbamate hydrochlorideand 0.9 g. of sodium chloride were added in the same way as described inExample 6, but the solution was protected from airoxygen by working innitrogen atmosphere. 0.05 g. of sodium pyrosulphite were then dissolved,whereafter 1 mg. of adrenaline was added. The pH was adjusted to 4.0 byadding sodium hydroxide. Sterilized water was added to 100 ml.

EXAMPLE 8 Pharmaceutical jelly containing N-n-butyl-3-piperidyl-2-chloro-6-methylphenylcarbamate hydrochloride To ml. of distilled water,4 g. of N-nbutyl-3- piperidyl-2-chloro-6-methylphenylcarbamatehydrochloride were added. To this solution 4 g. of methylcellulose wereadded while stirring and when all methylcellulose was dissovled asolution of 50 mg. of chlorhexidine diglyconate in 10 ml. of water wasadded and the volume was adjusted to ml. by addition of distilled water.

EXAMPLE 9 Pharmaceutical ointment containing N n butyl-3-piperidyl-2-chloro-6-methylphenylcarbarnate Equal amounts (27 g. ofeach) of polyethyleneglycol 300 and polyethyleneglycol 1540 were meltedtogether with 19 g. of polyethyleneglycol 3000 at 60 C. Then 25 g. ofpropyleneglycol and finally 2 g. N-n-butyl-3-piperidyl-Z-chloro-6-methylphenylcarbamate base were added and theointment was homogenized.

EXAMPLE 10 Eye drop preparation containing N-n-butyl-3-piperidyl2-chloro-6-methylphenylcarbamate hydrochloride To 100 ml. of distilledwater are added 2 g. of N-nbutyl-3-piperidyl2-chloro-6-methylphenylcarbamate hydrochloride. To this solution 0.5 g.of methylcellulose are added while stirring. When all methylcellulosewas dissolved 2 mg. of benzalkonium chloride were added. The solutionwas filtered through a cotton filter, filled into vial and autoclaved.

EXAMPLE 1 1 Month gargle preparation containing N n butyl 3- piperidyl 2chloro 6 methylphenylcarbamate hydrochloride g. of N-n-butyl-3-piperidyl2-chloro-6-methylphenylcarbamate hydrochloride and 1.0 g.methyl-p-oxibenzoate were dissolved in 1000 ml. distilled water. 0.2 g.of peppermint oil, 1.5 g. of Tween 80 and 20.0 g. of glycerine wereadded. The solution was filtered and filled into bottles.

EXAMPLE 12 Suppository preparations containing N n butyl 3- piperidyl2-chloro-6-methylphenylcarbamate base N-n-butyl-3-piperidyl 2chloro-6-methylphenylcarbamate base 30 mg.; hydrocortinsone acetate 5mg.; zinc oxide 0.4 g.; witep sol W 25 to 2.25 g.

Material for 200 suppositories was used. The suppository base was meltedat 50 55 C. and the N-n-butyl-3- piperidyl-Z-chloro 6methylphenylcarbamate base dissolved. The powders were added and themixture was stirred, homogenized and filled into molds.

EXAMPLE 13' Aerosol spray containing N-n-butyl-3-piperidyl 2-chloro-6-methylphenylcarbamate base N-n-butyl-3-piperidyl 2chloro-6-methylphenylcarbamate base 4.1 g.; cetylpyridine chloride 0.008g.; ethanol 7.8 ml.; polyethylene glycol 400 18.3 ml.; flavor q.s.

The N n butyl-3-piperidyl-2-chloro 6-methylphenylcarbamate base wasdissolved in the mixture of ethanol and polyethylene glycol. The othercomponents were dissolved. 32.2 g. of the solution was filled intoaerosol bottles. 32.5 g. of trichlorofiuormethane and 17.5 g. ofdichlordifiuormethane were added and the bottles were capped with valvesgiving 50 mg. of N-n-butyl-3-piperidyl- 2-chl0ro-6-methylphenylcarbamatein each dose.

We claim:

1. An anesthetic pharmaceutical preparation containing an effectiveanesthetic amount of a compound selected from the group consisting ofcarbamate of the general formula:

10 r NHC 0-0 References Cited UNITED STATES PATENTS 2,762,842 9/1956Hafiiger et al. 260553 3,103,515 9/1963 Zaugg et al. 260292 FOREIGNPATENTS 717,212 10/ 1954 Great Britain 260294.3 717,213 10/1954 GreatBritain 260294.3 717,214 10/1954 Great Britain 260294.3 770,129 3/1957Great Britain 260294.3 772,807 4/1957 Great Britain 260294.3 576,421 5/1959 Canada 260294.3

OTHER REFERENCES Dahlbom eta1.: Acta Chem. Scand. 11, 1350-4 (1957).Hutton et al.: J. Org. Chem. 20, 808-12 (1955). Sekeva et al.:Experienta, 11, 275-6 (1955). I Sekeva et al.: Arch. Pharm. 291, 122-5(1958).

JEROME D. GOLDBERG, Primary Examiner US. Cl. X.R. 424274 @1 3 UNITEDSTATES PAT NT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,632,766Dated April 97 Inventor(s) Johan Richard Dahlbom, John Lars GunnarNilsson It: is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Col. l line 26, Change "5.0" to 4.0

Col. E, lines 27,- 31-35, "h, i, 1;" should be italicized. Col. 7 line59, Change "was" to were Col. 7 line 71, Change "N-n" to N-n Col. 7 line75, Change :tfi-n" to N- n Col. 9 line 38, Change of 'carbarr late'" toC01. 10 line 10, Change "aceptable" 1 7 0 Col. 10 line 11, Change "R toR References cited-other references:

Change "Experienta" to of a canbamate acceptable Experientia Signed andsealed this 8th day of August 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

